ARVD/C – a short review

DR.R SASINTHARSR, CARDIOLOGY

JIPMER

ARVC

Inherited progressive CMP characterized by fibro-fatty replacement of RV +/- LV myocardium that predisposes patients to life threatening arrhythmia and heart failure

• Prevalence: 1/5000 to 1/2000• M:F = 3:1• Leading cause of SCD in young athletes, 10% of death

from it• Median age of onset of symptom 29• First presentation can be SCD

1. Clinical presentations of ARVC – diverse• Syncope• Progressive heart failure (HF)• Ventricular tachyarrhythmias• Sudden cardiac death (SCD)

2. Predominantly affects the RV with fibrofatty replacement pathologically 3. LV involvement usually late (typically the posterior lateral wall) - 10% of patients

Genetics of ARVC• Family hx +ve in 30-50% of cases• AD inheritance but highly variable penetrance and

expressivity• AR form in Naxos disease• “Defective desmosome hypothesis”

Marcus et al. JACC 2013

DSP

DSC2

DSG2PKP

JUP

Clinical impact of genotyping

• Genotyping in Preclinical phase• Possibility to identify genetically affected

relatives before a malignant clinical phenotype manifests

• Focussed prevention strategy and Timely therapy with b-blockers and/or ICD is highly effective in prevention of SCD

Clinical course : 4 phases

1. Concealed phase (Mild or absence of RV structural abnormalities but SCD can still occur)

2. Overt electrical disorder (Palpitation syncope PVC VT with LBBB)

3. RV failure (RV pump failure due to progressive loss of RV myocardium)

4. Bi-ventricular failure (LV involvement similar to DCM)

Diagnosis of ARVC: from past to present

McKenna et al initially proposed international TF criteria for the diagnosis of ARVC in 1994

Marcus et al revised them in 2010• Major criteria : 2 TFC points • Minor criteria : 1 TFC point. • ≥4 TFC points Definite ARVD• 3 TFC points Borderline ARVD • 2 TFC points Possible ARVD

Incorporation of quantitative parameters by echo or MRI yields high specificity (90–98% for major criteria)

Non-invasive1. ECG2. Signal averaged ECG3. Echocardiogram 4. MRI5. Holter monitoring6. Genetic analysis

Invasive 1. RV angiography2. RV endomyocardial

biopsy

Epsilon wave in V1–3 and diffuse T wave inversion in V1–6. The morphology of clinical VT - LBBB and superior axis

ECG screening and pre-symptomatic diagnosis

• The annual incidence of SCD in athletes decreased approximately by 90%, from 3.6/100 000 personyears in the pre-screening period to 0.4/100 000 person-years in the late screening period

Signal-averaged electrocardiogram (SAECG) depicting 3+ according to Task Force criteria.

Imaging in ARVC• Diagnostic challenge • Overemphasis to Imaging may be problematic• RV Imaging – not the gold standard

Predilection areas

1. Subtricuspid region2. Basal RV free wall3. LV posterior wall

TRANSTHORACIC ECHOCARDIOGRAPHY

• 1st line imaging modality• Ideal screening tool• Follow-up• Should be performed using current ASE

guidelines• North american multidisciplinary study :

enlarged RVOT – 100% of probands

RV dilatation

• Not specific to ARVC• Physiologic adaptation to high-intensity

exercise• RV enlargement in ARVC - a/w increased risk

of SCD and ventricular arrhythmias in athletes• ARVC vs Normal adaptaion

RV function• Challenging by TTE• A4C FAC – useful correlate of global RV

function• FAC <33% - sensitivity 55% and specificity 95%

Other morphologic abnormalities• Trabecular prominence

Most frequently noted morphologic abnormality (54%)

NEWER ECHOCARDIOGRAPHIC TECHNIQUES IN ARVC

1. RV myocardial performance index• Independent of geometric assumptions• Reduced RV MPI in ARVC probands, even

when global RV function as assessed by FAC was normal

Yoerger DM, Marcus F, Sherrill D, et al. Right ventricular myocardial performance index in probands from the multicenter

study of arrhythmogenic right ventricular dysplasia (abstr). J Am Coll Cardiol 2005;45:147A.

2. Intravenous TTE contrast3. TAPSE with M mode or tissue doppler4. 3D TTE5. RV free wall myocardial velocity, strain, and strain rateBy a. TDI b. Speckle tracking

CMR

• RV wall thinning• RV outflow tract enlargement,• Trabecular disarray • Fibrofatty replacement • Ventricular dilation and • Global or regional systolic dysfunction

LGE – indicative of fibrosis (prevalence : 88%)Intramyocardial hyperintense signal in T1W spin echo imaging in 22-100%

ROLE OF CMR IN ARVC DIAGNOSISEmphasis on functional abnormalities.

(95% specificity)

(79% to 89% sensitivity)

ROLE OF CMR IN EARLY DIAGNOSIS AND RISKSTRATIFICATION

• Wall motion abnormalities in the RV subtricuspid region - 94% of subjects with CMR structural involvement

• Fatty infiltration of LV posterior wall – in ARVD mutation carriers

te Riele AS, James CA, Philips B, et al. Mutationpositive ARVD: the triangle of dysplasia displaced.

J Cardiovasc Electrophysiol 2013;24:1311–20

Rastegar et al

ROLE OF CMR IN RISK STRATIFICATION OF ARRHYTHMIAS

• Previous studies : severe RV dysfunction and LV involvement predict adverse outcome in ARVC

• Sustained arrhythmias during follow-up coincide with structural abnormalities on CMR

• CMR - independent predictor of ventricular arrhythmia among 369 consecutive patients undergoing evaluation for ARVD/C.

• Normal CMR No events in 6 yr f/u

te Riele AS, Bhonsale A, James CA, et al.Incremental value of CMR in arrhythmic risk stratification of ARVD-associated

desmosomal mutation carriers. J Am Coll Cardiol 2013;62:1761–9.

Deac et al

COMPUTED TOMOGRAPHY

• Tissue characterizationPossible use of CT • Evaluation of claustrophobic patients• Subjects with frequent ventricular

extrasystoles leading to severe arrhythmia artifacts on CMR

• Serial evaluation of ICD carriers

RV angiography

• May depict sacculation, segmental contraction impairment, and variable trabecular patterns

• Remains the gold standard for structural assessment in some laboratories

Endomyocardial Biopsy

• Assessment of transmural fibrofatty infiltration by EMB

• Potential risk of free wall perforation • Possibility of false negative results owing to

the nature of segmental involvement.• Guiding EMB based on the low voltage area

identifiable on electroanatomic mapping - yield higher diagnostic sensitivity

Voltage mapping

3D electroanatomic bipolar voltage maps. Marcus et al

Normal ARVC

EP studies by programmed stimulation (PVS)

• Pivotal role in evaluating the vulnerability of ventricular tachyarrhythmias

• Also provide clues for the diagnosis of ARVC

1) Presence of PVCs with ≥ 1 couplet 2) VT or NSVT with LBBB after excluding RVOT VT by high dose isoproterenol (45 mg/min) infusion help in making the diagnosis of ARVC in the early stage of disease (sensitivity 91.4% ; specificity 88.9%)Denis et al

• Incidence of appropriate ICD discharge did not differ between patients who were and were not inducible at PVS for either 1° and 2° prevention of arrhythmic sudden death, regardless of indication for ICD implant

•Inducibility of VT or VF at pre-implantelectrophysiologic study demonstrated a trendtoward statistical significance for subsequent appropriate device intervention

Corrado et al

Witchter et al

•VT induction was the most significant independent predictor of appropriate ICD firing

Roguin et al

DDRisk stratification in patients with ARVC

Corrado et al Bhonsale et al

Major determinants in predicting sudden death and worse outcome

• Young age• Prior cardiac arrest• Fast and poorly tolerated VT with different

morphologies• Syncope• Severe RV dysfunction, heart failure with LV

involvement• Familial occurrence of juvenile sudden death

Factors influence disease progression and the arrhythmic episodes

Progressive nature of ARVD, incomplete genetic penetrance and variable manifestations

• Endurance training – induce RV enlargement and/or VT

• Summer season [Chung et al]

MANAGEMENT OF ARVC

Aim : to prevent the occurrence of ventricular tachyarrhythmias and SCD

1. Antiarrhythmic drugs (AADs)2. AICD 3. Radiofrequency catheter ablation4. Heart transplantation

Asymptomatic and healthy gene carriers

• To refrain from participating in physical exercise and sport activity

• Prophylactic B blockers ?

Patients with well tolerated and notlife threatening ventricular arrhythmias

•Either sotalol or amiodarone (alone or in combination with Beta-blockers)•Catheter ablation

ICD implantation• 28% reduction in 5 year mortality in males with an ICD

[Hodgkinson et al ]

• Average incidence of ICD therapies for VF/VFL-4%/year in 84 patients with definite or probable ARVD [Bhonsale et al. ]

• Current guidelines -- Class I indication

Family members : • It is unknown whether and when the family members should

receive an ICD implantation for 1 ̊ prevention• ICD implantation for family members with SCD, or undiagnosed

syncope when ventricular tachyarrhythmias cannot be excluded as cause of syncope after OMT -- Class II indication

Antiarrhythmic medication

• Empirical AADs should be considered for patients with a propensity to the occurrences of VT/VF

• No prospective study elucidating and comparing the efficacy of individual AADs

• Wichter et al : Sotalol- effective ; Class I AADs – ineffective

• North American ARVC Registry, Marcus et al: 1. Amiodarone significantly reduced the risk of clinically relevant ventricular arrhythmias 2. Sotalol increased the risk of ventricular tachyarrhythmias 3. Beta-blockers did not influence the risk

EAM & Catheter ablation of ventricular tachyarrhythmias

• Characteristics of re-entrant VT similar to ischemic VT

• Acute success rate- 50 to 90% • Induced by iso/PVS• Morphology compared to clinically-

documented VT • Stable VT – both activation and entrainment

mapping done

Pathogenesis of arrhythmogenic substrates and VT isthmuses

• Fibrofatty replacement : Epicardium gradually toward the endocardium

• Extent of fibrofatty infiltration epicardium > endocardium

• Longer and delayed epicardial activation sequence

• Layered activation of epicardial scar in ARVD/C rather than transmural activation of RV

• Arrhythmogenicity of epicardial VT circuits dominantly

Substrate mapping of endocardium and epicardium

• 3D navigation systems – more reliable method• 3D color-coded voltage mapping - tricuspid valve

region and the RV outflow tract • Endocardial substrate bipolar voltage cutoff -0.5-

1 mV• Epicardial substrate bipolar voltage cutoff - 1 mV• Distribution of epicardial scar is more extensive

than scar identified endocardially

Epicardial bipolar voltage mapping and the distribution of abnormal electrograms, consisting of isolated and fractionated

late potentials

• Pacing maneuver -facilitate recognition of delayed components of electrograms through different direction of wavelet propagation

• Nonmappable VTs unstable VT, multiple reentrant circuit, and nonsustained VT

• Endocardial – initial strategy • Endocardial - prevention of VT recurrence could

be achieved in only 25–53% of cases • Endo+Epi – freedom from VT in 45–84.6%

Heart transplantation

• Pts with extensive HF or drug-refractory ventricular tachyarrhythmias unresponsive to other invasive interventions

Load-reducing therapy

Conclusion

• Early investigation and risk stratification essential for successful Mx

• Accurate diagnosis based on cardiac imaging, ECG, histopathology, family history, EP study, and genetic screening

• With understanding of the underlying substrate properties, and improvement of navigation system, mapping, and epicardial ablation techniques, the prognosis of VT ablation in ARVD/C has improved tremendously